Add time:07/17/2019         Source:sciencedirect.com

In this paper, a liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed and validated for the simultaneous analysis of metabolic stability and metabolite profiling of 1-[4-(2-methoxyethyl) phenoxy]-3-[[2-(2-methoxyphenoxy) ethyl]amino]-2-propanol hydrochloride (TJ0711 HCl), a new vasodilatory β-blocker. Multiple reaction monitoring (MRM) was used as a survey scan to quantify the parent compound and to trigger the acquisition of enhanced product ions (EPI) for the identification of formed metabolites. In addition, comparison between MRM-only and MRM-information dependent acquisition-EPI (MRM-IDA-EPI) methods was conducted to determine analytical variables, including linearity, limit of detection (LOD), lower limit of quantification (LLOQ), as well as intra-day and inter-day accuracy and precision. Results demonstrated that MRM-IDA-EPI quantitative analysis was not affected by the addition of EPI scans to obtain qualitative information during the same chromatographic run, compared to MRM-only method. Thereafter, metabolic stability and metabolite identification of TJ0711 HCl were investigated using human liver microsomes (HLM) by the MRM-IDA-EPI method. The in vitro metabolic stability parameters were calculated and t1/2, microsomal intrinsic clearance (CLint), as well as hepatic CL, were 13.0 min, 106.5 μL/min/mg microsomal protein, and 1082.2 mL/min, respectively. The major formed metabolites were also simultaneously monitored and the metabolite profiling data demonstrated that this MRM-IDA-EPI method was capable of targeting a large number of metabolites, in which demethylation and hydroxylation were the principle metabolism pathways during the in vitro incubation with HLM.

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